Exogenous administration of glial cell line derived neurotrophic factor (GDNF) reduces ischemia-induced cerebral infarction. Cerebral ischemia induces gene expression of GDNF, GDNF-receptor a-1 (GFRa-1) and c-Ret, suggesting that a GDNF signaling cascade mechanism may be involved in endogenous neuroprotection during ischemia. In the present study, we examined if this endogenous neuroprotective pathway was altered in Gfra-1 deficient mice. Since mice homozygous for the Gfra-1 deletion (-/-) die within 24 h of birth, stroke-induced changes in the levels of Gfra-1 mRNA were studied in Gfra-1 heterozygous Gfra-1 (+/-) mice and their wild-type (+/+) littermates. The right middle cerebral artery was transiently ligated for 45 min in anesthetized mice. Animals were killed at 0, 6, 12 and 24 hours after the onset of reperfusion and levels of Gfra-1 mRNA were measured by in situ hybridization histochemistry. Previously, we showed that Gfra-1 (+/-) mice are more vulnerable to focal cerebral ischemia. In the present study, we found that basal levels of GFRa-1 mRNA were similarly low in cortex and striatum in adult Gfra-1 (+/+) and Gfra-1 (+/-) mice. Ischemia/reperfusion induced up-regulation of Gfra-1 mRNA in the lesioned and contralateral sides of cortex and striatum in both Gfra-1 (+/+) and GFRa-1 (+/-) mice. However, ischemia/reperfusion induction of Gfra-1 mRNA was significantly higher in the cortex of wild type mice, as compared to Gfra-1 (+/-) mice. Moreover, the increased expression of Gfra-1 in striatum after reperfusion occurred earlier in the Gfra-1 (+/+) than in the Gfra-1 (+/-) mice. These results indicate that after ischemia, there is a differential up-regulation of Gfra-1 expression in Gfra-1 (+/+) and Gfra-1 (+/-) mice. Since GDNF has neuroprotective effects, the reduced up-regulation of Gfra-1 in Gfra-1 (+/-) mice at early time points after ischemia suggests that the responsiveness to GDNF and GDNF receptor mediated neuroprotection is attenuated in these genetically modified animals and may underlie their greater vulnarability.